Indivior PLC, the pharmaceutical company that manufactures the opioid overdose antidote Opvee (nalmefene), has published new research showing that its product performed favorably compared to naloxone, in simulations of overdose involving fentanyl and carfentanil.
A pre-proof was published in the journal Neuropharmacology on June 6. Three of the four authors work for Indivior, and the fourth works for a software simulation company but was paid by Indivior for this study.
Nalmefene is an opioid antagonist, the same class of medication as naloxone (and naltrexone, better known by brand name Vivitrol). Narcan and all the similar-looking nasal sprays use naloxone, except for Opvee, which in 2023 became the first Food and Drug Administration-approved opioid overdose reversal product to use nalmefene. Since then Indivior has been aggressively marketing Opvee as the only antidote that works quickly enough and lasts long enough to reverse overdose involving fentanyl. But it’s been about a year since the last Indivior-funded study claiming to support this.
Nalmefene lasts five or six times longer than naloxone—which reverses fentanyl overdose just fine—and as such, harm reduction organizations across the US have rejected Opvee out of concern that it will increase risk of fatal overdose, and at the very least cause unnecessary suffering, by increasing precipitated withdrawal.
Precipitated withdrawal is what happens when someone is given a higher dose of opioid antagonist than was necessary. An appropriate dose—which can be achieved by titrating with IM or IV naloxone—doesn’t kick all the opioid off their brain’s receptors, just enough so that they can resume breathing on their own again. An unnecessarily high dose throws them into withdrawal—but instantly, rather than over the course of hours like withdrawal that happens naturally, and until it’s out of their system they won’t be able to get well by using opioids again the way they normally would. Because of this, the risk is that the person will use a significantly larger dose of opioids in a desperate attempt to relieve the symptoms, and die as a result of that overdose.
“Reduced duration of brain hypoxia” is important, but less important in this context.
The study found that in simulations involving “various intravenous doses of fentanyl and carfentanil” where no antidote was administered, cardiac arrest was predicted in between 18 percent and 90 percent of people who use opioids, and between 40 percent and 96 percent of people who don’t use opioids. Nalmefene nasal spray reduced this risk more than naloxone nasal spray, and also reduced “duration of brain hypoxia.”
Though it’s a common misconception that the way to keep someone alive while you wait for the antidote to kick in is by giving them chest compressions—rescue breathing is the important thing—it is technically true that cardiac arrest is often a part of overdose, because cardiac arrest happens to everyone once they die. The study’s authors confirmed to Filter that “the incidence of cardiac arrest can be viewed as a surrogate measure of death in the absence of any intervention such as cardiopulmonary resuscitation.” But not whether any of its findings correspond to likelihood of surviving an overdose, or to any sort of impact on the overdose victim’s wellbeing.
The second outcome, reduced duration of brain hypoxia, is definitely important, but in contexts other than what’s being referred to in this study.
Let’s say two people begin overdosing at the same time, and Person 1 is administered naloxone at the exact same moment that Person 2 is administered nalmefene. If the nalmefene reverses the overdose before the naloxone, that would be reduced “duration of brain hypoxia.” What the term doesn’t reflect is that Person 1 would have been revived a few moments later just fine, while Person 1 is now at higher risk of dying later that day. Oxygen deprivation can cause brain damage, but the risk of brain damage incurred between the time it takes nalmefene to kick in and the marginally longer time it takes for naloxone to kick in isn’t really the crisis that overdose antidotes are trying to address here.
You don’t need to rapidly deliver a high concentration of naloxone in order to restore someone’s breathing.
“The rapid onset of respiratory depression following a synthetic opioid overdose makes prompt intervention critical for a successful rescue,” the study states. “Intravenous (IV) naloxone remains the standard for the reversal of an opioid overdose in the emergency department because it rapidly delivers high naloxone concentrations needed to restore respiration in the face of a potentially lethal synthetic overdose and can be titrated to effect to minimize the risk of precipitated withdrawal symptoms in patients with a history of opioid use. However, the IV option is often unavailable in a community setting where first responders rely on either intramuscular (IM) or intranasal (IN) products.”
Saying that intravenous is the standard because it delivers a lot of naloxone very quickly is somewhat at odds with saying it’s the standard because it allows the dose to be titrated to avoid giving someone too much, which is because only one of these things is true. You don’t need to rapidly deliver a high concentration of naloxone in order to restore someone’s breathing.
Second, intramuscular naloxone can be titrated just as effectively, so the fact that community first responders (people who use fentanyl and/or syringe service program peer workers, generally) don’t have IV naloxone isn’t really a problem. The only overdose-reversal products that introduce substantial risk of precipitated withdrawal are Narcan and the other formulations of naloxone that can’t be titrated. And Opvee.
“The opioid supply is changing so rapidly that, for practical utility, this feels dated,” Maya Doe-Simkins of Remedy Alliance, the only source of affordable naloxone for many harm reduction groups in the US, told Filter. “Paying attention to … precipitated withdrawal is more important than ever. Cardiac arrest, in simulations, maybe that’s great info and we’d want to know in the big picture, but it’s not something to focus on right now.”
Back when the unregulated opioid supply was still heroin-based, overdose was something that unfolded over a longer period of time. If someone was overdosing and you didn’t have any naloxone and didn’t want to call the cops, you could probably drive across town to get some and still reverse the overdose without a problem.
Fentanyl peaks in your system much quicker than heroin; overdose can cause someone to stop breathing in a matter of minutes. That’s what “the importance of rapid intervention” means in real life—being able to respond to an overdose as soon as you notice it, which is why it’s so critical for everyone in drug-user communities to have access to naloxone and carry it on their person rather than storing it somewhere.
Image via United States Department of Health and Human Services